Apparatus and method for controlling contrast enhanced imaging procedures

ABSTRACT

A system for delivery of a medium having ultrasound contrast enhancement agents therein to a patient includes a pressurizing device for pressurizing the medium, a fluid path connecting the pressurizing device to the patient and a concentration sensor in communication with the fluid path. The concentration of the contrast enhancement agents is measured by the concentration sensor during injection of the medium into the patient to assist in controlling the delivery system and/or an imaging procedure.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a division of co-pending Application Ser. No.09/267,238, filed on Mar. 12, 1999, the contents of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates generally to the control ofcontrast enhanced imaging procedures, and, more particularly, toapparatuses, systems and methods for controlling an imaging procedure inwhich contrast agents are delivered to a patient.

[0003] Ultrasound imaging creates images of the inside of the human bodyby broadcasting ultrasonic energy into the body and analyzing thereflected ultrasound energy. Differences in reflected energy are made toappear as differences in gray scale or color on the output images. Aswith other medical imaging procedures, contrast enhancing fluids (oftenreferred to as contrast media) can be injected into the body to increasethe difference in the reflected energy and thereby increase the contrastdisplayed in the image (that is, the image contrast) viewed by theoperator.

[0004] For ultrasound imaging, the most common contrast media containmany small bubbles (sometimes referred to as microbubbles) suspendedtherein. The difference in density of bubbles when compared to water,and thus their difference in sound transmissivity, makes small gasbubbles excellent means for scattering ultrasound energy. Small solidparticles can also serve to scatter ultrasonic energy. Such particlesare typically on the order of 1 to 10 microns (that is, 10⁻⁶ to 10⁻⁵meters) in diameter. These small particles can pass safely through thevascular bed and, in some cases, traverse the pulmonary circulation.Contrast agents are also used for non-vascular applications such asassessment of tubal patency in gynecological applications.

[0005] Contrast media suitable for use in ultrasound are supplied in anumber of forms. Some of these contrast media are powders to whichliquid is added just before use. The powder particles cause gas bubblesto coalesce around them. The powder must be mixed with a liquid, and themixture must be agitated with just the right amount of vigor to obtainthe optimum creation of bubbles. Another type of contrast medium issupplied in a liquid form that requires hypobaric or pressureactivation. A third type of contrast medium is a liquid that is agitatedvigorously. There are no solid particles to act as nuclei, but theliquid is a mixture of several liquid components that make relativelystable small bubbles. A fourth type of contrast medium uses “hard”spheres filled with a gas. These contrast media are typically suppliedas a powder that is mixed with a liquid. The goal is to suspend thespheres in the liquid without breaking them. Even though such sphereshave a shell that is hard compared to a liquid, they are very small andrelatively fragile. It is also possible for the solid particlesthemselves to act to scatter ultrasonic energy, but the acousticalproperties of the solid spheres are not as different from water as thoseof a gas. However, solid particles have the advantage that they are muchmore robust and long lasting.

[0006] Suspended or dispersed entities such as microbubbles (liquid orgas), microspheres and solid particles suitable to enhance ultrasonicimaging contrast are referred to herein as contrast enhancementagents/particles. With these agents there are several problems,including: (1) Variations in the preparation process (mixing, agitation,pressure activation) can lead to variations in microsphere or particleconcentration that affect the resulting imaging procedure; (2) Someagents deteriorate with time after preparation, causing theconcentration of the microbubbles or particles to decrease; and (3)Microbubble agents can also be adversely affected by pressure before orduring administration, causing microbubble destruction by increasing gasdiffusion rates or damage to the encapsulation shell from delivery orpressure effects. This may also affect the microbubble concentration.

[0007] Contrast enhancement agents also enhance other modes ofultrasonic imaging. For example, when the microbubbles, microspheres orparticles are carried along in the blood stream, the reflected energy isDoppler shifted. This Doppler shift allows an estimation of the speed ofblood flow. Bubbles can also be excited so that they radiate ultrasonicenergy at a harmonic of the incident ultrasonic energy. This harmonicimaging with the use of contrast medium can be used to increase theeffectiveness of the contrast agent.

[0008] After mixing/preparation as described above, the contrast mediumis drawn into a syringe or other container for injection into thepatient. Typically, the fluid is injected into the vein in the arm ofthe patient. The blood dilutes and carries the contrast mediumthroughout the body, including to the area of the body being imaged(that is, the region-of-interest or ROI). As mentioned above, thecontrast medium can also be injected into other body cavities or tissuesas necessary for diagnostic or therapeutic activities.

[0009] It is becoming more common for a microprocessor-controlled,powered injector to be used for injecting the contrast medium. The useof such powered injectors has the benefit of maintaining a consistentflow over a long time, thereby providing a consistent amount of contrastmedium in the blood stream. If there are too few contrast enhancementparticles per unit volume in the flow, however, there will beinsufficient image enhancement and the diagnosis cannot be made. If toomany contrast enhancement particles are present, too much energy isreflected, resulting in blooming or saturation of the ultrasoundreceiver.

[0010] Thus, although a power injector can inject contrast medium at aconstant flow rate, there must generally be a constant number ofcontrast enhancement agents per volume of fluid injected to provide aconstant image contrast. Because a gas is significantly less dense thanwater and other liquids, however, gas bubbles will rise in a liquid. Therate of rise is related to the diameter of the gas bubble. This densitydifference provides a useful tool to quickly separate large bubblescreated during the initial mixing. However, the small bubbles desiredfor image enhancement will also rise slowly. Solid particles, on theother hand, will tend to settle or sink because most solids are denserthan water. Many minutes can elapse between the initial mixing of thecontrast medium and the injection into the patient, or the injectionitself may be several minutes in duration. If the concentration ofparticles changes, the image contrast will be degraded as mentionedabove.

[0011] There are also many other reasons why the number of contrastenhancement agents per volume of a certain contrast medium (and therebythe image contrast) can vary during an injection procedure. For example,the initial mixing may not have resulted in a homogeneous dispersion orsuspension. Likewise, bubbles or microspheres of certain contrast mediacan be destroyed under conditions experienced in mixing/preparation,storage or delivery of the contrast media.

[0012] It is, therefore, very desirable to develop systems and methodsto control the concentration of contrast enhancing agents delivered to apatient in an ultrasound imaging procedure.

SUMMARY OF THE INVENTION

[0013] The present invention provides systems, apparatuses and methodsfor delivery of a medium having, for example, ultrasound contrastenhancement agents therein to a patient. The present invention includesa pressurizing unit, such as a pump, for pressurizing the medium, afluid path connecting the pump to the patient and a sensor incommunication with the fluid path.

[0014] In an embodiment, the present invention includes a system fordelivery of a medium with contrast enhancement agents therein into apatient. The system includes a container to hold the medium, apressurizing device for pressurizing the medium in the container, afluid path connecting the pressurizing device to the patient, and asensor in communication with at least one of the container, thepressurizing device or the fluid path. The sensor is operable to measurea property of the contrast enhancement agents.

[0015] The properties that may be measured by the sensor include, butare not limited to, concentration and size distribution. Further, forexample, the concentration of the contrast enhancement agents may bemeasured by the sensor before or during injection of the medium into thepatient.

[0016] In a preferred embodiment, the sensor measures the properties ofthe contrast enhancement agents to control the preparation of themedium, the delivery of the medium and/or an imaging procedure carriedout in conjunction with delivery of the medium.

[0017] The contrast media contains contrast enhancement agents whichinteract with the energy beamed into the body for creation of the image.The energy can be ultrasonic or electromagnetic. Common electromagneticenergies include X-rays and light. The contrast enhancement agentsinclude but are not limited to microbubbles—with or without a solid coreor nucleus, microspheres with relatively rigid shells filled with gas orliquid, liposomes with relatively flexible shells filled with gas orliquid, solid micro-particles, or microspheres of a liquid that are notmiscible with the liquid in the contrast media. Any contrast mediainvolving two immiscible materials or different phases of material couldbenefit from this invention. Contrast media where the molecules of thecontrast enhancing material dissolve in the liquid of the contrast mediacan benefit from this invention to the extent that they are mixed fromtwo different phases or to the extent that they might separate duringstorage or use.

[0018] The present invention preferably further includes a communicationunit for transmitting data corresponding to the measured concentrationor other property of the contrast enhancement agents. A user interface(including, for example, a display unit) in communicative connectionwith the communication unit may be used to provide the concentration orother data to an operator. The user interface can also be adapted forinput of data by the operator.

[0019] Preferably, the present invention also includes a processing unitin communicative connection with the communication unit. This processingunit preferably includes a control unit adapted to transmit a controlsignal based at least in part on the concentration or other datareceived from the communication unit.

[0020] The present invention may also include a pump controller tocontrol the pressurizing of the injection medium. The pump controller ispreferably in communicative connection with the processing unit so thatthe operation of the pump controller is responsive to (that is,controlled by) the control signal from the processing unit.

[0021] The present invention preferably further includes an imaging unitsuch as an ultrasound scanning unit to produce a contrast enhanced imageof the patient. The imaging unit is preferably in communicativeconnection with the processing unit so that the operation of the imagingunit is responsive to or controlled by the control signal from theprocessing unit. The imaging unit can also be adapted to transmit asignal corresponding to properties of the image to the processing unitso that other delivery operations can be controlled based upon thesignal from the imaging unit.

[0022] The present invention may further include an agitation mechanismto agitate the medium before or during injection of the medium. Theagitation mechanism is preferably in communicative connection with theprocessing unit so that the operation of the agitation mechanism isresponsive to or controlled by the control signal received from theprocessing unit.

[0023] In the case, for example, that the contrast enhancement agentscomprise microbubbles or microspheres suspended in the medium, thepresent invention may further include a contrast enhancement agentconcentration regulator that is operable to dilute, damage or destroy acontrolled portion of microbubbles or microspheres to control theconcentration thereof. The bubble concentration regulator is preferablyin communicative connection with the processing unit so that theoperation of the bubble concentration regulator can be responsive to orcontrolled by the control signal from the processing unit.

[0024] The present invention also provides a method of delivering amedium with contrast enhancement agents therein into a patient. Themethod comprises the step of measuring a property (for example, theconcentration or size distribution) of the contrast enhancement agentsbefore or during delivery of the medium to the patient to control thedelivery.

[0025] Further, the present invention provides a method of preparing amedium with contrast enhancement agents therein. The method comprisesthe step of measuring the concentration or other property of thecontrast enhancement agents during preparation of the medium to assistin properly preparing the medium. Likewise, the present inventionprovides a system for preparing a contrast medium with contrastenhancement agents therein comprising a mixing container, an agitationmechanism for agitating the contents of the mixing container and asensor adapted to measure the concentration or other property of thecontrast enhancement agents in the container.

[0026] The present invention still further provides a fluid path elementto cooperate with a system for delivery of a medium with contrastenhancement agents therein into a patient. The system includes apressurizing device for pressurizing the medium, a fluid path connectingthe pressurizing device to the patient, and a sensor, such as aconcentration sensor, in communication with the at least one of thepressurizing device or the fluid path. The concentration or otherproperty of the contrast enhancement agents is measured by the sensor(before or during delivery of the medium into the patient). The fluidpath element preferably includes a conduit through which the fluid canflow, and a coupler to physically mate with the concentration sensor.The coupler is preferably fabricated from an injection-molded polymericmaterial.

[0027] Known and repeatable concentration of contrast enhancement agentssuch as microbubble agents is important from preparation to preparationof contrast media to gain consistent imaging results. The presentinvention can operate in conjunction with an injection system (automatedor manual) to measure the concentration and/or size distribution of suchcontrast enhancement agents before or during injection. The resultantinformation/signal on agent concentration and/or size distribution canbe used, for example, to correct images for diagnostic utility or beused in real-time with an automated injection system to dynamicallycontrol flow rate and more precisely control agent delivery and thevascular concentration of the agent. Concentration and/or sizedistribution information can also be used to control microbubbleconcentration and/or size in the delivery path either by mixing orcontrolled bubble regulation/destruction before the agent is injectedinto the patient. By delivering known concentrations and sizedistributions of agents, the time course of enhancement can be observed,opening the way to measuring dose response and to indicator dilutionapplications of ultrasound contrast. At the very least, the measurementcan be used to indicate when an enhancement agent has been damaged ormay be ineffective, preventing a useless or sub-optimal imagingprocedure.

[0028] The present invention and its attendant advantages will befurther understood by reference to the following detailed descriptionand the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029]FIG. 1 illustrates an embodiment of a contrast enhancement agentconcentration measurement system of the present invention.

[0030]FIG. 2 illustrates an embodiment of a delivery system of thepresent invention.

[0031]FIG. 3 illustrates an embodiment of a fluid path element adaptedto optimally transmit energy to the fluid for measurement ofmicroparticle concentration.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Many enhancement agents typically have a microbubbleconcentration on the order of approximately 1×10⁸ to 1×10⁹ particles perml. Mean bubble size for currently available transpulmonary agentstypically range from approximately 2 to 10 μm. Microbubble concentrationand size distribution influence the image enhancement achieved. Thepresent inventors have discovered that certain techniques such asoptical and ultrasound techniques can be used to measure contrastenhancement agent concentration and/or size distribution to bettercontrol numerous aspects of the operation of a contrast delivery system.

[0033]FIG. 1 illustrates a system 10 including a syringe 20 and aconnector tube 30 as part of the fluid path. As clear to one skilled inthe art, however, it is possible to apply the systems and methods of thepresent invention to any type of fluid delivery system (for example, aperistaltic pump, a drip bag, a gear pump, etc.), whether automated ormanually operated.

[0034] In FIG. 1, syringe 20 contains the contrast medium/enhancementagents including bubbles 40 and includes a moveable piston 50 forpressurizing the contrast medium. Connector tube 30 delivers the fluidfrom syringe 20 to the injection site on the patient, typically throughan intravenous catheter. Connector tube 30 may be attached to syringe 20with a connecting device such as a Luer fitting (not shown). Syringe 20and connector tube 30 are preferably sterile to preventbio-contamination or infection of the connected patient.

[0035] A sensor, for example, including an ultrasound emitter 60, ispreferably attached to the wall of connector tube 30 to insonate thecontents of connector tube 30 with ultrasound energy. Because it ispreferable to make reliable contact to the wall of connector tube 30 totransmit the ultrasonic energy, a custom molded section of the fluidpath may be used as will be discussed in detail later in relation toFIG. 3. It is also possible for elements of the sensor to be integratedwith the connector tube or as part of a disposable element within thefluid path.

[0036] In this embodiment, the sensor also preferably includes anultrasound receiver 70 positioned on the side of the connector tube 30opposite emitter 60 to receive the transmitted ultrasound energy.Emitter 60 and receiver 70 can also be combined together as a singleunit that, for example, clips onto connector tube 30. This arrangementis configured for operation in a transmissive mode. The functions ofemitter 60 and receiver 70 can also be performed by a single unit whichoperates in a reflective mode. The reflective mode is basically howultrasonic imaging units operate. A second emitter 80 can be used toinsonate the fluid path to take advantage of beat frequency resonanceeffects of microbubbles 40 (described in further detail below). Orelement 80 could operate as a receiver to receive some of the scatteredenergy.

[0037] A signal processor 90 (for example, including a microprocessor)can generate the transmitted ultrasound signal(s), amplify the receivedsignal, determine the concentration of the agent 40 taking intoconsideration the arrangement that is used, and forward a control signalto, for example, an attached powered injector 100 and/or an operatordisplay 110. The control signal can be used in various ways. One way isto increase the flow rate of the injection (ml/sec) if the concentrationof the particles in the medium decreases so that a constant number ofparticles is delivered per second.

[0038] Several different types or modes of sensors or transmit/receivecouplings are possible for use in the present invention depending on theelements that are included in the system. Several configurations oroperating modes are described below for illustrative purposes.

[0039] Transmissive Operation

[0040] Transmissive operation is suitable for use with contrastenhancing agents that contain solid particles or exhibit ultrasoundsignal attenuation as a function of bubble concentration and/or sizedistribution. In this configuration, ultrasound energy is transmittedfrom an ultrasound emitter 60 and the transmitted energy is receiveddirectly across the fluid path with an ultrasound receiver 70. Thepresence of microbubbles 40 will scatter some of the transmitted energyso that only a portion of the transmitted energy is received dependingon the microbubble concentration. (In FIG. 3, beams 119, 120, and 121are scattered. Beam 122 is transmitted.) The decrease in transmissivityis also referred to as beam attenuation.

[0041] For enhancement agents that contain solid particles, in additionto scattering energy, the particles also absorb energy, which occurs bya mechanism referred to as “relative motion”. (This is shown in FIG. 3,beam 123.) The change in attenuation caused by relative motion increaseslinearly with particle concentration and the square of the densitydifference between the particles and surrounding medium. Parker, K. J.et al., “A Particulate Contrast Agent with Potential for UltrasoundImaging of Liver”, Ultrasound in Medicine and Biology, Vol. 13, No. 9,p. 555, 561 (1987).

[0042] In one preferred embodiment, the transmitting and receivingelements can be physically attached together so that the tubing or otherfluid path element can be secured between the two elements. Alternately,the two elements could be placed on a clip-on type assembly that clampsonto the tubing.

[0043] The ultrasound signal intensity of emitter 60 is preferablysufficient to measure changes in transmissivity or reflection/response,but not so great as to damage microbubbles 40 by excessive energy fromthe transducer of emitter 60. Otherwise the measurement itself canaffect the microbubble concentration of the medium. However, if desired,emitter 60 can be operated with sufficient power to selectively destroymicrobubbles 40 to control the concentration thereof.

[0044] Reflective Backscatter Operation

[0045] In this technique, the reflected backscatter from transmittedultrasound energy is measured to determine microbubble concentration.Ultrasound energy is transmitted and the amount of backscatter that isreceived is measured. In FIG. 3, beam 119 is backscattered. Ultrasoundenergy may be transmitted and received by the same element, anultrasound transmitter/receiver transducer. This mode is similar to, butmuch simpler than, the configuration used by ultrasound scanners. Only asingle transmit/receive element is needed and there is no scanning ofthe element by either physical movement or phased array techniques. Theamount of backscatter received from the transmitted energy is measuredby signal processor 90 to determine the concentration of microbubbles 40in the agent. When many bubbles 40 are present, the level of backscatterenergy will be high. The amount of backscatter that is present is afunction of a number of parameters including, for example, the liquid,bubble size, and frequency of ultrasound energy used, in addition tobubble concentration.

[0046] The capability of a substance to cause backscatter of ultrasoundenergy also depends on a number of other characteristics of thesubstance such as its ability to be compressed. Different substances arecompared using a particular measure of the ability of a substance tocause backscatter known as “scattering cross section”. The scatteringcross section of a particular substance is proportional to the radius ofthe scatterer, and also depends on the wavelength (i.e., 1/frequency) ofthe ultrasound energy and on other physical properties of the substance.See U.S. Pat. No. 5,611,344. When many bubbles 40 are present, the levelof backscatter energy will be high. Operation in a reflectivebackscatter mode has the added advantage that the Doppler shift from themoving bubbles can be measured if the vector of incidence of theultrasonic energy has a sufficiently large component in the direction ofthe fluid flow. This then provides a measurement of flow rate. Thisinformation can be useful for flow rate control in non-syringe basedpumps or for detecting conditions such as a fluid blockage or flowstall.

[0047] Reflective Harmonic Operation

[0048] A reflective harmonic operational configuration is similar to theconfiguration used for reflected backscatter operation, only the mediais insonated by one frequency and backscatter is received at an harmonicor combination of harmonics of the transmitted frequency. (A harmonic ofa frequency f is an integer multiple of f.) Depending on their size, atsome frequencies, microbubbles 40 resonate with the applied ultrasoundfield. Bubbles 40 grow larger and/or become smaller in sympathy with theoscillations of pressure caused by the incident sound. For large enoughpower levels, the resonant oscillation in the ultrasound field containsnon-linear motion of the bubble wall. This non-linear motion createsharmonic sounds that can be detected by an ultrasound transducer.

[0049] Harmonic mode imaging is used with some enhancement agents thatshow a distinct and relatively large response at harmonics of someexcitation frequency. With this configuration, the transmitting elementpreferably has sufficient bandwidth to transmit and receive harmonicsand sufficient sensitivity to detect the harmonic response. It may bepreferable to have separate transmit and receive elements in thisembodiment that are matched to the transmit and receive frequencies,respectively.

[0050] In addition, it is possible to gather information on bubbleconcentration as a function of bubble size in a liquid by sweeping thetransmitting frequency and observing the harmonic response over a rangeof frequencies. The amplitude of the harmonic response is related to theconcentration of bubbles of a certain size, since the resonant frequencyof an individual bubble is a function of its size. This could beespecially useful for use with harmonic imaging or drug deliveryapplications.

[0051] Configurations that are based on backscatter or harmonicmeasurement techniques may be more suitable for agents that contain amicro-particle substrate for the microbubbles (for example, Levovist™available from Schering AG of Berlin, Germany). Because the substratemay still remain after bubbles are destroyed, backscatter techniquesthat look for response from the bubbles may give a better indication ofbubble concentration than transmissive methods that can be affected bysolid particles in the agent.

[0052] Reflective Beat Frequency Operation

[0053] Reflective beat frequency operation involves detecting thenon-linear sum and difference beat frequencies produced by microsphereswhen two impinging signals with non-identical frequencies are combinedby mixing. See U.S. Pat. No. 5,601,086. The technique applies tomicrosphere concentration in a body fluid or in a general fluid.

[0054] Referring to FIG. 3, transmitted energy from ultrasound emitter60 is directed through connector tubing 30 to the fluid. A secondemitter 80 is used to transmit energy at the same region at a secondfrequency that is also an approximate resonant frequency of themicrospheres. The microspheres interact and emit the sum and differenceof the two frequencies. Receiver 70 is used to detect the sum anddifference frequencies that are a function of microbubble concentration.

[0055] Optical Diffusion Approach

[0056] Another operational approach is to detect changes in microbubbleconcentration by an optical diffusion measurement. In this application,electromagnetic radiation of many wavelengths (frequencies), even downto DC current, may be used. As with ultrasound, optical scatter is afunction of the number of particles and their effective cross sectionalscattering area. Again, FIG. 3 can be used for this discussion. Acollimated light beam from an optical source or emitter 60, such as alaser diode or other light emitting device, can be coupled through arelatively transparent adapter 35 to a tube or container (segment of thefluid path) filled with the enhancement agent. The optical diffusion orscatter could be measured with an optical sensor/receiver orientedtoward the container, such as a phototransistor element 70 or 80. Thephototransistor may be connected to the input of an amplifier (notshown) to obtain a useable high level output signal.

[0057] For optimal scatter measurement, the optical sensor 80 can beoriented perpendicular to the beam from the optical source 60 so thatthe energy from the direct beam is not measured, and only the scatteredcomponent is measured. The chamber used is preferably as transparent aspossible so as not to introduce any additional diffusion or reflectivemirror effects from its interior surface. To eliminate potential noiseeffects of ambient light sources, the optical source and sensor arepreferably shielded with an enclosure to absorb reflected light within.Alternatively, the optical source can be pulsed and the receiver can usea chopper amplifier, also known as a lock-in amplifier, to measure smallchanges in diffusion and reject measurement variations from ambientsources. Also, by using both detectors 70 and 80 it is possible to takethe ratio of the scattered to the transmitted light and remainindependent of variations in the intensity of the light source. This isimportant because light sources generally degrade over time andfluctuate with power supply variations.

[0058] Several other methods are possible for performing concentrationmeasurements or particle size measurements for small agents in asuspension. These methods include laser reflection, diffraction,turbidity and photon migration approaches.

[0059] For particle substrate microbubble agents such as Levovist, it isbelieved that there will be some base component of scatter resultingfrom the particle substrate in the mixture and some additional scatterresulting from the microbubbles attached to the substrate. As thebubbles diffuse into the surrounding liquid or are destroyed, theoptical diffusion properties of the media may change. It may be possibleto obtain an adequate estimate of microbubble concentration by measuringonly the concentration of the substrate particulate through scattermeasurements. For agents that are relatively high in particle andmicrobubble density, it may be necessary to use a transparent containerthat has relatively small dimensions so that the scattered light is notreabsorbed by the surrounding volume of media. Another solution is todilute the media by some known amount to reduce the degree of opticalscatter that occurs or to increase the intensity of the optical source.It may also be possible to measure microbubble concentration changes bychanges in transmissivity or optical density of the media. This approachwill require an optical path length through the media that is longenough for changes in optical density to be detected, but short enoughso that some signal gets through for the measurement.

[0060] Fluorescence of the microparticles is another mechanism thatcould be used to measure the concentration of the microparticles.Electromagnetic radiation of one wavelength is transmitted into thefluid, and emissions of another wavelength are emitted by themicroparticles.

[0061] The methods disclosed above transmit energy into the fluid andmeasure transmission and/or reflection of that energy at some position.FIG. 3 illustrates these modes of measurement in general. In FIG. 3,element 60 is the source of the energy (ultrasound or electromagneticenergy). The energy can be received by elements 70 and/or 80 and/or 60.Element 35 couples the energy in a repeatable fashion into the fluid. Ina preferred embodiment, element 35 is injection molded to have preciseand repeatable dimensions. Normal extruded tubing is not typicallyrepeatable enough, although precision extrusion techniques are possible.Alternatively, several paths (such as using both 60 to 70 and 60 to 80)can be used to compensate for extrusion variability. Element 35 can, forexample, be molded into the neck of a syringe or can be part of theconnector at either end of the tube used to conduct the fluid to thepatient. It might also be possible to simply insert mold element 35around the fluid path tubing 30. A preferable material for element 35 ispolycarbonate, which is clear and easily injection moldable. Forultrasound transmission, polypropylene can also be used.

Delivery System with Contrast Enhancement Agent ConcentrationMeasurement and Operational Control

[0062]FIG. 2 illustrates a block diagram of another embodiment of adelivery system 210 for delivering contrast enhancement agents (forexample, a suspension of bubbles 220 in a fluid) to a patient 230. Inthis embodiment, a syringe or pressurizing vessel 240 drives fluidthrough a fluid path 250. Fluid path 250 may pass through a bubble orcontrast enhancement agent concentration regulator 260 that can affectthe enhancement properties of the agent by, for example, selectivelydestroying bubbles 220. Bubbles 220 may be destroyed, for example, byinsonating the fluid with ultrasound energy, generating localtemperature or pressure changes in the media or by mechanical agitation.

[0063] The ability to destroy microbubbles in the fluid path opensopportunities to improve and better control the imaging procedure. Asdiscussed above, bubbles can be destroyed by insonating the agent withsufficient ultrasound energy, especially if the energy is at a resonantfrequency of the bubbles of interest. Since mechanical resonance of abubble wall is a function of bubble size, it may be possible with theproper power and frequency settings to selectively decrease theconcentration of bubbles of a certain size. Such selective destructionallows control of the bubble size distribution. Microbubbles could bedestroyed in the fluid path as part of a strategy to maintain a constantagent concentration.

[0064] Fluid path 250 continues through a concentration sensor 270similar to that described in connection with FIG. 1, and then continueson through a patient interface 280 to an injection site on patient 230.The output of sensor 270 passes to a processing unit 290 which may, forexample, include a concentration measurement and signal processing unit294 to provide concentration data for use by delivery system 210 and anelectronic control system 296. A signal corresponding to theconcentration data may be sent from control system 296 to any number ofdevices in delivery system 210 including, for example, an imaging unitsuch as an ultrasound scanner 300. The control signal can be used, forexample, to adjust the image (for example, by increasing or decreasinggain), to provide concentration information as part of documentationand/or to assist with diagnosis during the imaging procedure.Information can also preferably be sent from imaging unit 300 to controlsystem 296 or processing unit 290 to, for example, control other devicessuch as, for example, an agitation mechanism 310 (including, forexample, a mechanical stirrer 314) which homogenizes the concentrationof particles in the fluid, a powered injection control unit 320 and/orconcentration regulator 260. If the agitation mechanism were operatedvigorously enough, the concentration of particles in the fluid couldeven be increased.

[0065] Agitation mechanisms suitable for use in the present inventionare disclosed in a U.S. patent application entitled AGITATION DEVICESAND DISPENSING SYSTEMS INCORPORATING SUCH AGITATION DEVICES and filed onMar. 12, 1999, the disclosure of which is incorporated herein byreference. In that regard, several commercial agents now availablerequire some kind of agitation or mixing for preparation. These include,but are not limited to: Albunex™ and Optison™ available from MolecularBiosystems, Inc. of San Diego, Calif., and Levovist™.

[0066] The concentration measurement techniques of the present inventioncan be used during initial preparation of the medium or during aninjection procedure to determine whether agitation/preparation issufficient or as feedback for agitation or mixing control. Some agents,such as Levovist™, are known to precipitate or separate over time insome of the larger concentrations (for example, 400 mg/ml).Concentration measurement techniques can be used, for example, to detectsuch separation and restart or increase agitation to help reduceprecipitation effects.

[0067] Other agents, such as EchoGen™ available from SONUSPharmaceuticals, Inc. of Bothell, Wash, require hypo-baric (pressure)activation before use. Typically, the agent is placed in a hand syringe,the fluid path is sealed and the plunger is pulled back and suddenlyreleased, generating a pressure transient within the media. During thisprocess, the perfluoro-compound in the agent converts to very smalldroplets (200 to 600 nm) and microbubbles. If this procedure is notperformed adequately, image enhancement may be degraded and patienttolerance may decrease. Microbubble and/or droplet concentration can bemeasured after pressure activation for these units to ensure that theagent was prepared correctly and to give information on the remainingpost-activation contrast enhancement agent life.

[0068] Concentration sensor 270 or multiple sensors can be locatedanywhere on the fluid delivery path from, for example, attachment to thebarrel of syringe or pressurizing vessel 240 to patient interface 280.Attachment of a concentration sensor to the syringe or to a storagecontainer wherein preparation of the contrast medium occurs can, forexample, enable measurement of contrast enhancement agent concentrationduring preparation of the contrast medium, regardless of the mode ormechanism of initial preparation (for example, including hypobaricpreparation or simple agitation). If concentration sensor 270 is locatednear the patient injection site at the end of fluid path 250, near thepatient interface 280, one can account for microbubble degradationeffects from shear rate, temperature and other delivery effects. Sincesensor 270 preferably does not require direct contact with the contrastenhancement agent, a coupling piece can be made as a disposable part ofa tubing set for convenience in attaching sensor 270 and to maintainsterility with patient interface 280. The sensing area is preferably aknown volume or accessible area of the agent surface located on fluidpath 250, as was discussed above in relation to FIG. 3.

[0069] As discussed above, control system 296 of processing unit 290 mayuse concentration data and other information to activate or controlagitation mechanism 310, such as mechanical stirrer 314, so that thecontrast enhancement agent is mixed homogeneously. Information fromcontrol system 296 can also be sent to injection controller 320 todynamically adjust flow rate as a way to control the concentration ofthe contrast enhancement agent as it enters patient 230. Theconcentration and other data can also be sent to an optional userinterface 330 so that the operator may receive information about theagent being delivered. Data, such as control parameters or algorithms,can also preferably be sent from user interface 330 to processing unit290.

[0070] In summary, contrast enhancement agent concentration or otherdata can be used in a variety of applications. The systems describedabove, for example, may be used in a stand-alone embodiment with anoperator interface or with a powered injection system to providereal-time feedback to the injector system for dynamic control of flowrate and delivery concentration. If the system is used in a stand-aloneembodiment, it can be used with a simple operator interface to indicatewhen the contrast enhancement agent is properly prepared or is degraded.Contrast enhancement agents can degrade with time, for example, as aresult of gas diffusion out of the bubble or a breakdown in theencapsulation mechanism. It has also been observed with some agents (forexample, Levovist) that pressure from injection or blockage of the fluidpath can potentially decrease the effectiveness of the agent, presumablyby destroying some portion of the microbubbles. Agents can also losetheir effectiveness through improper preparation techniques such asexcessive agitation. Microbubble concentration is expected to decreaseas the agent degrades. The present invention can be used to quicklyindicate if there is a problem with the media, reducing the chance of anunnecessary procedure, or to indicate the remaining effective life ofthe contrast medium. Any number of visual, audio, or tactile means canbe used to display or present the concentration measurement to theoperator.

[0071] Real-time contrast enhancement agent concentration, sizedistribution or other data can assist in overcoming many current imaginglimitations such non-linear blooming and shadowing effects,scanner-to-scanner gain variability and physiological time delays beforeenhancement. Bubble concentration data can also be used to controlscanner settings, such as power, gain (for example, as a function ofmeasured pixel density), time between successive scans and as othersettings.

[0072] Time adjustments between scans may be especially useful because,for some agents, microbubbles are destroyed when insonated at sufficientultrasound power settings needed to image the surrounding tissue. As anexample, the time delay between scans can be automatically increasedupon detection of low contrast enhancement agent concentration in theregion-of-interest. This phenomenon may occur when additional time isrequired for a sufficient number of bubbles to congregate in theregion-of-interest to give adequate enhancement. Such control willreduce the amount of signal loss resulting from bubble destruction. Ascan interval controlled by contrast enhancement agent concentration canensure sufficient and uniform enhancement from scan to scan, given thepotential variability in injected concentration.

[0073] In the future, it is expected that microbubble agents may be usedfor more advanced diagnostic applications, such as site specific imagingand therapeutic applications, such as site specific or ultrasoundactivated drug delivery. The systems of the present invention will bevery useful in these applications in which the contrast enhancementagent concentration can be measured as part of monitoring delivered drugdose.

[0074] Although the present invention has been described in detail inconnection with the above embodiments and/or examples, it is to beunderstood that such detail is solely for that purpose and thatvariations can be made by those skilled in the art without departingfrom the spirit of the invention. The scope of the invention isindicated by the following claims, rather than by the foregoingdescription. All changes or modifications which come within the meaningand range of equivalency of the claims are to be embraced within theirscope.

What is claimed is:
 1. A method of preparing a medium with contrastenhancement agents therein, the method comprising the step of measuringa property of the contrast enhancement agents during preparation of themedium to assist in properly preparing the medium.
 2. The method ofclaim 1, further comprising the step of pressurizing the medium.
 3. Themethod of claim 1, further comprising the step of producing an image ofthe patient.
 4. The method of claim 1, further comprising the step ofagitating the medium.
 5. The method of claim 1 wherein the property ofthe contrast enhancement agents comprises at least one of concentrationand size distribution.
 6. A system for preparing a medium with contrastenhancement agents therein, the system comprising: a container includingthe medium; an agitation mechanism operably associated with thecontainer for agitating the medium; and a sensor adapted to measure aproperty of the contrast enhancement agents in the container.
 7. Thesystem of claim 6, further comprising a communication unit incommunication with the sensor, the communication unit operable tocommunicate data corresponding to the measured property of the contrastenhancement agents.
 8. The system of claim 7, further comprising aprocessing unit in communication with the communication unit, theprocessing unit operable to transmit one or more control signals basedat least in part on the measured property data.
 9. The system of claim8, further comprising a controller in communication with the processingunit, the controller operable to control the agitation mechanism atleast in part in response to the one or more control signals from theprocessing unit.
 10. The system of claim 6 wherein the property of thecontrast enhancement agents comprises at least one of concentration andsize distribution.
 11. The system of claim 7, further comprising a userinterface in communication with the communication unit to provide anindication functionally related to the measured property data to anoperator.
 12. A method of delivering a medium with contrast enhancementagents therein into a patient, the method comprising: measuring aproperty of the contrast enhancement agents; and controlling at leastone of the delivery of the contrast enhancement agents or an imagingprocedure carried out in conjunction with delivery of the contrastenhancement agents by selective destruction of contrast enhancementagents.
 13. The method of claim 12 wherein the selective destructionadjusts the concentration of the contrast enhancement agents.
 14. Themethod of claim 12 wherein the selective destruction adjusts the sizedistribution of the contrast enhancement agents.